This multidisiplinary SCOR studies causes, mechanisms, and treatments of human hypertension. The two previous SCOR grants defined the renin-angiotensin-aldosterone axis as a control system for blood pressure and electrolyte homeostasis and revealed a heterogeneity of essential hypertension. We demonstrated for the first time the active participation of the renin system in substantial fractions of essential hypertension, and showed that specific anti-renin system therapy is an important new antihypertensive strategy. This new SCOR will build on this knowledge. Basic biochemical studies will investigate prorenin and the angiotensin receptor, components least understood at the molecular level. Specific antibodies will provide probes for identification and quantification of these molecules. Their contribution to the pathogenesis of hypertension will be studied in animal models. The possible link of kallikrein to the renin-angiotensin system by regulating biosynthesis of renin from prorenin will be examined. Using renin profiling with our vasoconstriction-volume hypothesis we will define pressor mechanisms of toxemias of pregnancy and of collagen vascular diseases. Within renin subgroups of essential hypertension we will evaluate the pathogenic relation of changes in blood viscosity, catecholamines, and cardiac performance to blood pressure fluctuations of exercise and during continuous 24 hour monitoring. Cardiac pathophysiology will be defined using echocardiograpy and radionuclide angiography. Mechanisms for renin and aldosterone secretion and their interactions with ACTH-cortisol will be studied within renin subgroups. Our acquisition of key normative data also will allow us to apply renin profiling in a defined general population to approach the important questions of whether factors besides pressure are determinants of risk and relevant to designing more rational therapies. Thus, on SCOR will (1) expand knowledge of the biochemistry and physiology of the renin-angiotensin-aldosterone system, and (2) utilize definition of the renin axis' participation to assess the role of other variables in the heterogenous spectrum of hypertension.